Recently, as adipokine, a hormone secreted by fat, is known to play an important role in the occurrence of obesity-related complications in addition to known hematologic and metabolic factors, it is expected to be able to prevent or treat related diseases by adjusting their actions.
The importance of adipokine has been proven that severe insulin resistance, hyperglycemia, hyperlipidemia, fatty liver and the like have been found in animal models or humans having a congenital deficiency of adipose tissue. Representative types of the adipokines which have been known to date include leptin, adiponectin, TNF-alpha, Resistin, interleukin-6, plasminogen activator inhibitor-1, TGF-beta and the like (Nat Rev Immunol, 2011, 11(2), 85-97). Resistin was first discovered as a substance that mediates insulin resistance in obese mice.
Rodent resistin is secreted from adipocytes, which is presumed to be associated with obesity-related insulin resistance and type 2 diabetes (Nature, 2001, 409, 307-312). However, human resistin is quite different from rodent resistin. Human resistin is a cytokine that is secreted from monocytes and induces chronic inflammations. These chronic inflammations can lead to diabetes, obesity, liver disease, arteriosclerosis, rheumatoid arthritis and other cardiovascular diseases (Diabetes Metab J, 2013, 37, 404-414).
Resistin is a small protein of 12.5 Kda, and six monomers are linked to each other to form a hexamer (Science 2004, 304, 1154-1158). In a recent research, it was first discovered in the world that the receptor for human resistin is CAP1. Resistin increases cAMP via CAP1 and induces the expression of inflammatory cytokines via PKA, NFkB signaling system. Further, the research has reported that human resistin directly binds to CAP1 in monocytes, and involves in cAMP concentration, PKA activity and NF-kappaB-related transcription of inflammatory cytokines, and over-expression of CAP1 enhanced resistin-induced increased activity of cAMP-dependent signaling pathway. In particular, the transgenic mouse model has been shown that CAP1-over-expressed monocytes aggravated adipose tissue inflammation in transgenic mice. In contrast, it has been shown that inhibition of CAP1 expression abrogated the resistin-mediated inflammatory activity both in vitro and in vivo (Cell Metab, 2014, 19(3), 484-497).
Therefore, by developing a drug that effectively adjusts the action of resistin and CAP1, it is expected to be able to prevent and treat related diseases, especially cardiovascular diseases.